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1.
Proteins ; 92(1): 24-36, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37497743

RESUMO

Glioma is a type of tumor that starts in the glial cells of the brain or spine. Since the 1800s, when the disease was first named, its survival rates have always been unsatisfactory. Despite great advances in molecular biology and traditional treatment methods, many questions regarding cancer occurrence and the underlying mechanism remain to be answered. In this study, we assessed the protein structural features of 20 oncogenes and 20 anti-oncogenes via protein structure and dynamic analysis methods and 3D structural and systematic analyses of the structure-function relationships of proteins. All of these results directly indicate that unfavorable group proteins show more complex structures than favorable group proteins. As the tumor cell microenvironment changes, the balance of oncogene-related and anti-oncogene-related proteins is disrupted, and most of the structures of the two groups of proteins will be disrupted. However, more unfavorable group proteins will maintain and refold to achieve their correct shape faster and perform their functions more quickly than favorable group proteins, and the former thus support cancer development. We hope that these analyses will help promote mechanistic research and the development of new treatments for glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Oncogenes , Microambiente Tumoral
2.
Inorg Chem ; 61(31): 12067-12072, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35894746

RESUMO

Borates with tunable structure and property currently provide a new rich source for solid-state chemistry and materials science. Realization of property improvement via simple structural regulation is a rising hot spot of borate-based research. Herein, a new aluminoborate fluoride, Li3Cs6Al2B14O28F, with [B7O14] clusters was discovered, and it was found to melt congruently. The optimally aligned [B2O5] dimers within [B7O14] clusters make Li3Cs6Al2B14O28F an enhanced birefringence, which is about 4.3× higher than its congener compound Li4Cs3B7O14 with same [B7O14] clusters. Structural analysis and additional theoretical calculations have revealed the origin of enhanced optical anisotropy.

3.
Sensors (Basel) ; 22(9)2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35590926

RESUMO

The synthetic jet piezoelectric air pump is a potential miniature device for electronic cooling. In order to improve the performance of the device, a small-sized synthetic jet piezoelectric air pump is proposed in this work, which is mainly characterized by petal-shaped inlet channels. First, the structure and working principle of the piezoelectric vibrator and the proposed pump are analyzed. Then, three synthetic jet piezoelectric air pumps with different inlet channels are compared. These inlets are the direct channels, the diffuser/nozzle channels, and the petal-shaped channels, respectively. Furthermore, the performance of the synthetic jet piezoelectric air pump with the petal-shaped inlet channels is optimized by orthogonal tests. Finally, the simulation was used to investigate the heat dissipation capability of the synthetic jet piezoelectric pump. The experimental results show that among the three inlet channels, the petal-shaped channel can greatly improve the performance of the pump. The unoptimized pump with petal-shaped channels has a maximum flow rate of 1.8929 L/min at 100 V, 3.9 kHz. Additionally, the optimized pump with petal-shaped channels reaches a maximum flow rate of 3.0088 L/min at 100 V, 3.7 kHz, which is 58.95% higher than the unoptimized one. The proposed synthetic jet piezoelectric air pump greatly improves the output performance and has the advantages of simple structure, low cost, and easy integration. The convective heat transfer coefficient of the synthetic jet piezoelectric pump is 28.8 W/(m2·°C), which can prove that the device has a better heat dissipation capability.

4.
Gut ; 69(12): 2131-2142, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32241904

RESUMO

OBJECTIVE: Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD). DESIGN: Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity. RESULTS: A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats. CONCLUSION: Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients. TRIAL REGISTRATION NUMBER: This study was registered at ClinicalTrials.gov (NCT03010696).


Assuntos
Microbioma Gastrointestinal , Falência Renal Crônica/metabolismo , Metaboloma , Animais , Ácidos e Sais Biliares/metabolismo , Estudos de Casos e Controles , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Humanos , Masculino , Camundongos , Estresse Oxidativo , Ratos , Toxinas Biológicas/metabolismo , Uremia/metabolismo
5.
Angew Chem Int Ed Engl ; 56(1): 328-332, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27897364

RESUMO

Precisely engineering the electrical conductivity represents a promising strategy to design efficient catalysts towards oxygen evolution reaction (OER). Here, we demonstrate a versatile partial cation exchange method to fabricate lamellar Ag-CoSe2 nanobelts with controllable conductivity. The electrical conductivity of the materials was significantly enhanced by the addition of Ag+ cations of less than 1.0 %. Moreover, such a trace amount of Ag induced a negligible loss of active sites which was compensated through the effective generation of active sites as shown by the excellent conductivity. Both the enhanced conductivity and the retained active sites contributed to the remarkable electrocatalytic performance of the Ag-CoSe2 nanobelts. Relative to the CoSe2 nanobelts, the as-prepared Ag-CoSe2 nanobelts exhibited a higher current density and a lower Tafel slope towards OER. This strategy represents a rational design of efficient electrocatalysts through finely tuning their electrical conductivities.

6.
Med Sci Monit ; 22: 2006-12, 2016 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-27292522

RESUMO

BACKGROUND There is increasing evidence that adenosine triphosphate (ATP), a well-known neurotransmitter and neuromodulator in the central nervous system, plays an important role as an extracellular chemical messenger in the cochlea. MATERIAL AND METHODS Using a whole-cell recording technique, we studied the effects of ATP on isolated Hensen's cells, which are supporting cells in the cochlea, to determine if they are involved in the transduction of ions with hair cells. RESULTS ATP (0.1-10 µM) reduced the potassium current (IK+) in the majority of the recorded Hensen's cells (21 out of 25 cells). An inward current was also induced by high concentrations of ATP (100 µM to 10 mM), which was reversibly blocked by 100 µM suramin (a purinergic antagonist) and blocked by nifedipine (an L-type calcium channel blocker). After the cochleas were perfused with artificial perilymph solutions containing nifedipine and exposed to noise, the amplitude increase in the compound action potential (CAP) threshold and the reduction in cochlear microphonics was lower than when they were exposed to noise alone. CONCLUSIONS Our results suggest that ATP can block IK+ channels at a low concentration and induce an inward Ca2+ current at high concentrations, which is reversed by purinergic receptors. Nifedipine may have a partially protective effect on noise-induced hearing loss (NIHL).


Assuntos
Trifosfato de Adenosina/farmacologia , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/prevenção & controle , Nifedipino/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cobaias , Células Ciliadas Auditivas/metabolismo , Perda Auditiva Provocada por Ruído/metabolismo , Órgão Espiral , Técnicas de Patch-Clamp/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Distribuição Aleatória , Transdução de Sinais/fisiologia , Suramina/farmacologia
7.
Org Biomol Chem ; 13(32): 8723-8, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26179398

RESUMO

An unprecedented silver-catalyzed cascade reaction of tosylmethyl isocyanide (TosMIC) with propargylic alcohols for the efficient synthesis of (E)-vinyl sulfones has been developed where TosMIC plays a dual role as both the reactant in the allenylation of propargylic alcohols and the sulfonyl source.

8.
J Neurooncol ; 119(1): 91-100, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24842385

RESUMO

The present work evaluated the synergistic efficacy of an enediyne antibiotic lidamycin (LDM) plus temozolomide (TMZ) against glioma in vitro and in vivo. LDM plus TMZ inhibited the proliferations of rat glioma C6 cells and human glioma U87 cells more efficiently than the single usage of LDM or TMZ. In addition, LDM also potentiated the apoptosis inductions by TMZ in rat C6 cells and human U87 cells. Meanwhile, the results of TdT-mediated dUTP Nick End Labeling assay for subcutaneous U87 tumor sections indicated an enhanced apoptosis induction in vivo by LDM plus TMZ, which confirmed the high potency of the combination for glioma therapy. As determined by Western blot, apoptosis signal pathways in C6 cells and U87 cells were markedly affected by the synergistic alteration of P53, bax, procaspase 3, and bcd-2 expression. In both subcutaneous U87 xenograft and C6 intracerebral orthotopic implant model, TMZ-induced glioma growth suppression was dramatically potentiated by LDM. As shown, the combination therapy efficiently reduced the tumor volumes and tumor weights of the human glioma U87 xenograft. Kaplan-Meier assay revealed that LDM plus TMZ dramatically prolonged the life span of C6 intracerebral tumor-bearing rats with decreased tumor size. This study indicates that the combination of LDM with TMZ might be a promising strategy for glioma therapy.


Assuntos
Aminoglicosídeos/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Enedi-Inos/uso terapêutico , Glioma/tratamento farmacológico , Aminoglicosídeos/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Sinergismo Farmacológico , Enedi-Inos/farmacologia , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ratos , Transdução de Sinais/efeitos dos fármacos , Temozolomida
9.
Ying Yong Sheng Tai Xue Bao ; 35(1): 133-140, 2024 Jan.
Artigo em Zh | MEDLINE | ID: mdl-38511449

RESUMO

Wetlands store one third of global soil organic carbon (SOC) and are strongly affected by artificial drainage. The impact of drainage-induced water-table decline on carbon cycling in different wetlands, particularly microbial transformation processes, remains unclear. To address this knowledge gap, we collected soil samples from two typical wetlands of China (a nutrient-poor bog located in Dajiuhu and a nutrient-rich fen in Hongyuan) and conducted an incubation experiment with the addition of 13C-labeled glucose to analyze the effects of short- and long-term drainage on SOC decomposition, extracellular enzyme activity, microbial carbon use efficiency (CUE), and microbial carbon accumulation efficiency (CAE). The results showed that both short- and long-term drainage significantly increased SOC decomposition rates in both wetlands (from 1.47 µg C·g-1·h-1 in submerged soils to 2.47 µg C·g-1·h-1 in drained soils), microbial biomass carbon derived from glucose (from 0.21 mg C·g-1 to 1.00 mg C·g-1) and CAE (from 0.29 to 0.73), but did not alter CUE (ranging from 0.34 to 0.86). Long-term drainage increased α-glucosidase activity in the Dajiuhu wetland and decreased ß-glucosidase and phenol oxidase activities in the Hongyuan wetland. In conclusion, drainage enhanced the 'microbial carbon pump' and its efficiency in wetlands mainly via increasing microbial intracellular metabolism (including respiration), but also acce-lerated SOC decomposition.


Assuntos
Solo , Áreas Alagadas , Carbono/análise , Microbiologia do Solo , China , Glucose
10.
RSC Adv ; 14(3): 1813-1821, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38192308

RESUMO

Carbon quantum dots (CQDs), as a new type of fluorescent nanomaterial, are widely used in the detection of small molecules. Abnormal dopamine secretion can lead to diseases such as Parkinson's disease and schizophrenia. Therefore, it is highly significant to detect dopamine levels in the human body. Using discarded fruit peels to prepare carbon quantum dots can achieve the reuse of kitchen waste, reduce pollution, and create value. Nitrogen-doped carbon quantum dots (N-CQDs) were prepared using the hydrothermal method, with orange peel as the raw material. The fluorescence quantum yield of N-CQDs reached a high value of 35.37% after optimizing the temperature, reaction time, and ethylenediamine dosage. N-CQDs were characterized using various techniques, including ultraviolet visible (UV-vis) spectroscopy, fluorescence spectrophotometer (PL), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FT-IR). These analyses confirmed the successful doping of nitrogen in the CQDs. The DA concentration ranged from 0 to 300 µmol L-1, and the linear equation for fluorescence quenching of N-CQDs was F/F0 = -0.0056c + 0.98647, with an R2 value of 0.99071. The detection limit was 0.168 µmol L-1. The recovery and precision of dopamine in rabbit serum were 98% to 103% and 2% to 6%, respectively. The prepared N-CQDs could be used as a fluorescent probe to effectively detect DA.

11.
Front Vet Sci ; 11: 1375042, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38872802

RESUMO

The Chengkou mountain chicken, a native Chinese poultry breed, holds significant importance in the country's poultry sector due to its delectable meat and robust stress tolerance. Muscle growth and development are pivotal characteristics in poultry breeding, with muscle fiber development during the embryonic period crucial for determining inherent muscle growth potential. Extensive evidence indicates that non-coding RNAs (ncRNAs) play a regulatory role in muscle growth and development. Among ncRNAs, circular RNAs (circRNAs), characterized by a closed-loop structure, have been shown to modulate biological processes through the regulation of microRNAs (miRNAs). This study seeks to identify and characterize the spatiotemporal-specific expression of circRNAs during embryonic muscle development in Chengkou mountain chicken, and to construct the potential regulatory network of circRNAs-miRNA-mRNAs. The muscle fibers of HE-stained sections became more distinct, and their boundaries were more defined over time. Subsequent RNA sequencing of 12 samples from four periods generated 9,904 novel circRNAs, including 917 differentially expressed circRNAs. The weighted gene co-expression network analysis (WGCNA)-identified circRNA source genes significantly enriched pathways related to cell fraction, cell growth, and muscle fiber growth regulation. Furthermore, a competitive endogenous RNA (ceRNA) network constructed using combined data of present and previous differentially expressed circRNAs, miRNA, and mRNA revealed that several circRNA transcripts regulate MYH1D, MYH1B, CAPZA1, and PERM1 proteins. These findings provide insight into the potential pathways and mechanisms through which circRNAs regulate embryonic muscle development in poultry, a theoretical support for trait improvement in domestic chickens.

12.
Zhonghua Bing Li Xue Za Zhi ; 42(4): 248-51, 2013 Apr.
Artigo em Zh | MEDLINE | ID: mdl-23928532

RESUMO

OBJECTIVE: To study the pathologic features, diagnosis, differential diagnosis and molecular characteristics of intraductal tubulopapillary neoplasm of the pancreas (ITPN). METHODS: The clinical findings, morphologic features, immunophenotype (by EnVision method) and KRAS gene alterations (by reverse transcriptase-polymerase chain reaction) of 6 cases of ITPN encountered during the period from January, 2001 to June, 2010 were analyzed. RESULTS: There were altogether 2 males and 4 females. The mean age of the patients was 64 years. Gross examination showed that the tumors were located in large pancreatic ducts and appeared as polypoid nodules with ductal obstruction. Solid tumor nodules associated with adjoining dilated ducts were identified in one case. Histologically, the tumors were characterized by tubulopapillary growth pattern without luminal mucin. The tumor cells showed high-grade nuclear atypia with scanty intracytoplasmic mucin. Intraductal necrotic foci were frequently observed. Immunohistochemical study showed that the tumor cells expressed CK7 and CK19. Focal positivity for MUC5AC was demonstrated. Two cases expressed MUC1. The staining for MUC2 was negative. KRAS gene mutations were identified in 2 cases, with a single-amino-acid substitution in codon 12 (35G > A and 35G > T/34G > A). CONCLUSIONS: ITPN is a newly described pancreatic intraductal neoplasm and different from intraductal papillary mucinous neoplasm. ITPN is characterized by intraductal tubulopapillary growth pattern, severe cytologic atypia and scanty mucin secretion.


Assuntos
Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/patologia , Neoplasias Pancreáticas/patologia , Idoso , Substituição de Aminoácidos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Carcinoma Papilar/cirurgia , Feminino , Seguimentos , Humanos , Queratina-19/metabolismo , Queratina-7/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Mucina-5AC/metabolismo , Mucina-1/metabolismo , Pancreatectomia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento
13.
Angew Chem Int Ed Engl ; 52(43): 11303-7, 2013 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-24000196

RESUMO

Aldehyde Termination: A novel copper-catalyzed transformation from methyl ketones into aldehydes has been accomplished. This method is applicable to a wide range of aromatic and aliphatic methyl ketones and chemoselectively produces aldehydes, accompanied by the release of hydrogen (H2 ) and carbon dioxide (CO2 ) as by-products.

14.
Dalton Trans ; 52(13): 3942-3946, 2023 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-36919645

RESUMO

Borate has become a hot topic because of its rich structural chemistry and excellent properties for functional materials fields. The rearrangement of π-conjugated B-O units is key to enhancing the optical anisotropy, but it remains a challenge. Herein, by introducing [AlO4] tetrahedra, a new congruent melting aluminoborate LiCs3AlB7O14 with [B7O14] clusters was discovered. This work confirms that the introduction of [AlO4] tetrahedra can lead to the rearrangement of anionic framework of the borate system and thereby enhance the birefringence of LiCs3AlB7O14. The birefringence is about 4.1 times higher than that of its congener Li4Cs3B7O14 with the same [B7O14] clusters. Similarly, the effects of [AlO4] tetrahedra on the rearrangement of the B-O anionic framework are also demonstrated in other known borates.

15.
Nat Commun ; 14(1): 5052, 2023 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-37598219

RESUMO

Sphagnum wetlands are global hotspots for carbon storage, conventionally attributed to the accumulation of decay-resistant litter. However, the buildup of mineral-associated organic carbon (MAOC) with relatively slow turnover has rarely been examined therein. Here, employing both large-scale comparisons across major terrestrial ecosystems and soil survey along Sphagnum gradients in distinct wetlands, we show that Sphagnum fosters a notable accumulation of metal-bound organic carbon (OC) via activating iron and aluminum (hydr)oxides in the soil. The unique phenolic and acidic metabolites of Sphagnum further strengthen metal-organic associations, leading to the dominance of metal-bound OC in soil MAOC. Importantly, in contrast with limited MAOC sequestration potentials elsewhere, MAOC increases linearly with soil OC accrual without signs of saturation in Sphagnum wetlands. These findings collectively demonstrate that Sphagnum acts as an efficient 'rust engineer' that largely boosts the rusty carbon sink in wetlands, potentially increasing long-term soil carbon sequestration.


Assuntos
Eczema , Dermatopatias Bacterianas , Sphagnopsida , Ecossistema , Minerais , Carbono , Óxidos , Solo
16.
Int J Biol Macromol ; 244: 125291, 2023 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-37315670

RESUMO

Liver cancer can be primary (starting in the liver) or secondary (cancer that has spread from elsewhere to the liver, known as liver metastasis). Liver metastasis is more common than primary liver cancer. Despite great advances in molecular biology methods and treatments, liver cancer is still associated with a poor survival rate and a high death rate, and there is no cure. Many questions remain regarding the mechanisms of liver cancer occurrence and development as well as tumor reoccurrence after treatment. In this study, we assessed the protein structural features of 20 oncogenes and 20 anti-oncogenes via protein structure and dynamic analysis methods and 3D structural and systematic analyses of the structure-function relationships of proteins. Our aim was to provide new insights that may inform research on the development and treatment of liver cancer.


Assuntos
Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Proteínas , Abdome/patologia
17.
Virus Genes ; 44(3): 539-47, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22311430

RESUMO

The highly pathogenic Bombyx mori nucleopolyhedrovirus (BmNPV) has caused severe damages to sericulture in many countries, and the relationship between the pathogenicity of various BmNPV strains and their geographical evolution has been the topic of our interest. In this study, we isolated a new BmNPV strain from Thailand (BmNPV-Thai), based on the sequences of its conservative genes p10, p35, polh, egt and vp39. The BmNPV-Thai appears to have baculovirus repeated ORF (bro) genes different from four other well-known BmNPV strains of China (GD, CQ1), Japan (T3), and France (SC7); It only has bro-a, bro-c, and bro-d, but not bro-b and bro-e genes. These bro genes are localized only in the two subgroups highly homologous to their counterparts and their encoded BRO proteins differ mainly at their N-terminal amino acid residues. Phylogenetic analysis indicates that the evolution of the bro genes of the five BmNPV strains is not obviously associated with their geographic locations.


Assuntos
Bombyx/virologia , DNA Viral/genética , Genes Virais , Família Multigênica , Nucleopoliedrovírus/classificação , Nucleopoliedrovírus/isolamento & purificação , Animais , Análise por Conglomerados , DNA Viral/química , Dados de Sequência Molecular , Nucleopoliedrovírus/genética , Filogenia , Análise de Sequência de DNA , Tailândia
18.
J BioX Res ; 5(4): 181-196, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36618771

RESUMO

To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugated let-7a mimics (Chol-let-7a) and control mimics (Chol-miRCtrl) on hepatocellular carcinoma in vivo. Methods: The antitumor effects of two intravenous dosing regimens of Chol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in the Chol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then, let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution of Chol-let-7a and Chol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital. Results: Continuous treatment with Chol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in the Chol-miRCtrl and blank xenograft group (P < 0.01 and P < 0.01, respectively), while intermittent dosing with Chol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in the Chol-miRCtrl and the blank control group, respectively (P < 0.05 and P < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosing Chol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues; mild hypercellularity with dilated capillary lumens in the renal tissue; and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed that Chol-let-7a and Chol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration of Chol-let-7a and Chol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in the Chol-miRCtrl group. Finally, RT-PCR analysis showed that let-7a levels were significantly increased in Chol-let-7a-treated xenografts compared with Chol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001); however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively. Conclusions: Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy. Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future.

19.
Front Nutr ; 8: 756730, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712690

RESUMO

Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 µM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 µM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

20.
Exp Gerontol ; 150: 111376, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33905875

RESUMO

Gut microbial metabolites, SCFAs, were related with the occurrence and development of Parkinson's disease (PD). But the effects of different short-chain fatty acids (SCFAs) on PD and involving mechanisms are still undefined. In this study we evaluate the effects of three dominant SCFAs (acetate, propionate and butyrate) on motor damage, dopaminergic neuronal degeneration and underlying neuroinflammation related mechanisms in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. High (2.0 g/kg) or low doses (0.2 g/kg) of sodium acetate (NaA), sodium propionate (NaP) or sodium butyrate (NaB) were gavaged into PD mice for 6 weeks. High doses of NaA reduced the turning time of PD mice. NaB significantly reduced the turning and total time in pole test, and increased the average velocity in open field test when compared with PD mice, indicating the most effective alleviation of PD-induced motor disorder. Low and high doses of NaB significantly increased the content of tyrosine hydroxylase (TH) by 12.3% and 20.2%, while reduced α-synuclein activation by 159.4% and 132.7% in the substantia nigra pars compacta (SNpc), compared with PD groups. Butyrate reached into the midbrain SNpc and suppressed microglia over-activation. It inhibited the levels of pro-inflammatory factors (IL-6, IL-1ß and TNF-α) (P < 0.01) and iNOS. Besides, butyrate inhibited the activation of NF-κB and MAPK signaling pathways in the SNpc region. Consequently, sodium butyrate could inhibit neuroinflammation and alleviate neurological damage of PD.


Assuntos
Intoxicação por MPTP , Fármacos Neuroprotetores , Doença de Parkinson , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos , Ácidos Graxos Voláteis , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico
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